The finding — and following — of a killer (T-cell)

To really appreciate this story, we have to start at the end—simply put, there are people alive today because of a discovery made by an oncology fellow in the mid 1980s. And not just alive-these people are doing well, living healthy and full lives, sometimes symptom-free, because one doctor, Thomas P. Loughran Jr., M.D., professor of medicine and director, Penn State Hershey Cancer Institute, noticed something that no one else did.

“He’s a super doctor,” says George Graham of Bryn Athyn, Pennsylvania, one of Loughran’s patients who was unable to find appropriate treatment for large granular lymphocyte (LGL) leukemia at other facilities.

Loughran came to discovering LGL through what might be considered standard detective work—he reviewed patient labs and blood smears and kept looking. During a rotation at the University of Washington, Loughran saw a patient who was referred to the chief resident with an unknown illness and a history of recurrent fevers and infections. Upon reviewing the patient’s blood smear, Loughran was the first to notice that the patient’s white cells were granular lymphocytes that were larger than they should be. After reviewing the previous five years of records of the hematopathology laboratory directed by Marshall Kadin, M.D., he realized that other patients with similar histories also had the unusual white cell appearance. Loughran and Kadin went on to publish their discovery and subsequent research in the Annals of Internal Medicine.

“I was doing what you are supposed to do as a good doctor,” Loughran recalls of his time as a fellow at the Fred Hutchinson Cancer Research Center in Washington. “At that point, I didn’t have any real research background, but I was interested in it.” Loughran and his team next discovered that the LGL cells were clonal, copying themselves as they proliferated throughout the blood. “We were lucky because the next twenty patients actually didn’t have the clonal chromosomal abnormality.”

Hide and Seek with LGL

Patients with LGL leukemia are difficult to treat because the disease is difficult to diagnose. Unlike typical cancers that present with a large tumor or a decrease in organ function, LGL leukemia masks itself like several other illnesses. Because doctors don’t usually find it unless they are specifically looking for it, patients are often treated for something else, like rheumatoid arthritis (RA), anemia, and Felty’s syndrome.

“Before it was found, a lot of patients were diagnosed with chronic neutropenia, maybe anemia with unknown etiology, or unspecified leukemia. Others were simply undiagnosed with anything,” Loughran says. “Of the first twenty patients I found, none of them had an actual diagnosis or they were diagnosed with something like red cell aplasia.”

The basic hypothesis is that these cells are antigen-driven killer T cells. They are part of the immune system and are normally resting. When a virus is detected, the cells become activated and kill off the virus, and then they go back to resting. But in some cases, the cells remain active and clone, eventually developing into LGL leukemia. The exact cause for this remains unclear, but Loughran suggests that it may be triggered by a specific virus or a chronic infection.

“LGL leukemia causes inflammation that is very similar to rheumatoid arthritis,” Loughran says. “About a third of patients with LGL leukemia also have RA and another subset of patients has Felty’s. One study in England found that one-third of patients with Felty’s also has LGL leukemia. RA, Felty’s, and LGL are probably a continuation of the same cell process.” The tendency for patients with LGL to be misdiagnosed and mistreated allows the disease to progress, sometimes for years. Often, a patient’s symptoms are even vaguer, making them simply sick in general.

Finding the Right Treatment

“I was out of it for about a year,” Graham recalls. “I was just very weak, then spent a week in the hospital after a heart attack, but wasn’t feeling better.”

After seeing his regular doctor and being referred to an oncologist in the Philadelphia-area, Graham was finally diagnosed with leukemia. But the news that followed was even worse than the diagnosis.

“They told me to go home and get your things in order because you have three to four weeks to live,” Graham says. Unwilling to accept the scenario, Graham sought out second opinions and searched for treatment options at NIH and Penn, but came up empty. One of his physicians, however, was familiar with Loughran’s work and encouraged Graham to get in touch with him.

“He did the blood tests and said ‘you’re not going to die, we’re going to make a formula and you will start it next week,'” Graham remembers. “I started to feel better almost immediately, finding out that I’m not going to die. But then taking the medicine did wonders. Dr. Loughran told me ‘we can control this,’ and he did.”

Loughran says the treatment for LGL leukemia is primarily immunosuppressive. Since the cells are always active, medications are needed that will turn off or kill the LGL cells. Loughran generally treats patients with either low doses of methotrexate or cyclophospharmide, sometimes in combination with prednisone. “Chemotherapy doesn’t work in this disease as the cells are resistant to it,” Loughran says. After treatment, Graham went into complete remission and has been doing well for two years.

Tracking the Disease

The team at the Cancer Institute, including colleagues at University Park, is determined to find new ways to treat LGL leukemia. One recent project partnered Loughran with Réka Albert, professor of physics and biology at Penn State, and Ph.D. candidate Ranran Zhang as they developed a computer model to demonstrate the signaling of proteins and molecules in T-cells that develop into LGL leukemia. By identifying the structures behind the ongoing life of a T-cell, researchers hope to target that cause with medications and treatments that will eradicate them. Results of the study, which were published in Proceedings of the National Academy of Sciences, may have uncovered the two proteins that keep these cells alive. “Now, instead of testing all 500 proteins, we can test these two to give us an individualized approach to treatment,” Loughran says.

At the same time, Loughran has also established a registry for patients with LGL leukemia. The goals of the registry are to capture clinical information about patients, offer clinical studies, and provide treatment advice. The registry includes history from close to 500 patients throughout the world and tracks their treatment and prognosis.

As Loughran and his team continue to look for a cure by studying LGL leukemia’s infancy, some patients have been able to move past their treatments altogether. A case study in successful treatment, Graham now has six month follow-ups but no symptoms. He splits his time between Pennsylvania and Florida with occasional side trips to Italy to teach photography.

Just this past week I was diagnosed with lgl after two decades of blood issues. I had contracted bacterial dysentery while living in the Philippines in 1989 and after that have had problems, although they have become much more significant recently. Just this week, my bone marrow biopsy was done which will be back soon. I am interested in finding out more about your registry and how to deal with this. I am very happy with my hematologist/oncologist who seems very on top of the situation. Thank you.

Hi Otto,
Looks like I have not replied to you. We would be delighted to have you participate in our LGL registry. I will be sending a note to Ms. Kendall Thomas Baab, who is our LGL registrar. She can contact you. Others interested in our registry can contact her using the details below.
Best regards,
Tom Loughran

I am one of those diagnosed but asymptomatic group, diagnosed 6 years ago. Of possible interest, blood work has been off for 20 years. I have a chronic prostate infection that showed up about 10 years ago but I would guess I had it since my 20’s. I am 70. My father had very bad RA , but I have no RA. I have been practicing calorie restriction with optimal nutrition for 5 years. This is known to keep inflammation in you body low and activate P-53 among 100’s of other healthy things your body does in reaction to CR.

Thanks for your interest in the article. We do have a registry for LGL patients and would welcome your participation. It is of interest that there is a history of RA in your family, this is often the case.

Please see the address information above in comment replies for the registry contact.

13.Ofra G. | November 24, 2010 at 5:50 pm

I was terrified when my son was recently diagnosed with LGL. His doctor prescribed him cyclosporin, after 3 bone marrow biopsies and so much anguish! Now his white blood cell count went up after 2 weeks of treatment. I am interested to know if he is getting the right medicine.
thank you,

Just diagnosed today by my hemotologist. Chronic anemia and low white blood cells prompted further testing and this was the discovery. Would like to be a part of any research and information you have available.
Sincerely,
Amy B.
Beverly, MA

I am worried about the use of the high doses of predni-
sone as treatment for my husband’s LGL leukemia
because of all the future side effects of long term use.
It has reduced the weekly need for red blood cell trans-fusion from weekly to about monthly.

My father was just in your office yesterday with a diagnosis of LGL Leukemia. He was so impressed with your kind and gentle care.
Your resources are very informative, I will continue to educate myself on this disease. I appreciate you taking such good care of my father.

My 79 year old father was just diagnostic with this disease, he has had two transfusion of blood already in less than 3 months and has a follow up to see an Oncologist for the first time after numerous testing and a biopsy performed. I am really interested in finding out more information in regards to this disease. Thank you.

Is the registry still in place? My father was just diagnosed with LGL leukemia today. Other than the weakness others mention, he is without other symptoms. His oncologist says he will watch Dad without treatment unless something changes.

Dr. Loughran, could you please reiterate the importance of good nutrition for patients with LGL? could you recommend a resource to learn about the best diet for these patients. I would so appreciate it. Thank you and God bless you and your team.

Hi I have a 12 year old who is complaining of shortness of breath, bone pain, abdominal pain, very tired, she use to be very active and in the last year, she is always tired, should i be worried?
Tammy

27.Penn State Hershey | January 4, 2016 at 4:17 pm

Tammy –

It would be best for you to contact her primary care physician to get a diagnosis. They can then determine what the health issue may be and what specialist may be required if any.

Hello all! This was the article and the information in the comments that led me to start a dialog with Ms. Kendall and consult with Dr. Loughran a few months ago after I was recently diagnosed with T-Cell LGL Leukemia. Wonderful folks! I’m on my third chemo option (cytoxan) but very hopeful and upbeat while dealing with febrile neutropenia currently with ANC < 200.

After consulting with Dr. Loughran, I realized how rare this subtype of leukemia really is with not much information resources or patient to patient support system out there that were consistent, reliable and easily accessible through online. This inspired me to do something about it which led me to form a "closed" facebook group on LGL topics. This is aimed at creating a place for all of us with LGL to come together and support one another in whatever capacity possible and also to give ourselves a chance to share our experiences, feelings, knowledge, ideas and suggestions for improving our lives. The group is growing and we are looking for new members relevant to T-Cell LGL. The toughest part is how to effectively reach out to others with the same condition. Please consider joining at this short link: http://goo.gl/Ekzl8 or you may search for "LGL Group" directly on facebook. Information is power! Thank you.

My sincerer thanks to both Dr. Loughran and Ms. Kendall for giving me hopes and courage to tackle this LGL monster and for inspiring me to be an empowered patient!